Drugs that Mimic the Effect of Gene Mutations for the Prevention or the Treatment of Atherosclerotic Disease: From PCSK9 Inhibition to ANGPTL3 Inactivation.

BACKGROUND: Drugs mimicking natural beneficial mutations, including that for familial hypercholesterolemia (FH), might represent the future of hypolipidemic drug treatment. OBJECTIVE: The aim of this review is to review the properties and the effects of these drugs, which are either already commercially available or are in the process to be approved for the treatment of dyslipidemia. RESULTS: More than a decade ago, it was accidentally discovered that proprotein convertase subtilisin/kexin type 9 (PCSK9) loss-of-function mutations resulted in marked lifelong reduction of LDL-C and the incidence of cardiovascular disease (CVD). This provided the idea for a human anti-PCSK9 antibody. Along with dozens of phase II and III studies demonstrating unprecedented reductions in LDL-C levels, two large clinical trials established the substantial benefits of evolocumab and alirocumab on cardiovascular morbidity and mortality, on top of standard treatment. Evolocumab and alirocumab are now approved and used in clinical practice for the treatment of FH, statin intolerance, and high risk patients not achieving LDL-C targets. Anti RNA, small molecules, peptides and also protein fragments against PCSK9 are in phase 1 trials. Angiopoietin-like protein 3 (ANGPTL3) regulates lipid metabolism increasing triglycerides (TGs), remnants, and LDL-C. In a huge study, ANGPTL3 deficiency due to gene(s) loss-of-function was associated with substantial reductions in circulating TGs, LDL-C, and CVD. Evinacumab, an ANGPTL3 antibody, caused a dose-dependent reduction in fasting TG levels of up to 76% and LDL-C of up to 23% and CVD risk by 41%. There is also antisense oligonucleotide and micro-RNA- 27b (miR-27b) against ANGPTL3. Two naturally occurring mutations in apo3 gene, A23T and K58E, reduce TGs and CVD risk. A monoclonal antibody targeting apoC-III has the same effect. CONCLUSION: Mimicking the beneficial naturally happening mutations in lipid metabolism pathways with biological drugs is probably the future of hypolipidemic drug treatment.

The Role of Statins in the Management of Nonalcoholic Fatty Liver Disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and its advanced form non-alcoholic steatohepatitis (NASH) are the most common causes of elevated liver enzymes in the general population. NASH, and to a lesser extent NAFLD have been associated with increased liver-related, cardiovascular disease (CVD), and allcause mortality. No effective treatment is widely acceptable. OBJECTIVE: The purpose of this review is to summarize available data on the impact of statins on NAFLD and NASH. METHOD: A comprehensive review of the literature was performed to identify studies assessing the effect of statin use in NAFLD/NASH. RESULTS: Recent reports have shown that the use of statins in patients with elevated plasma aminotransferases may be beneficial. Post hoc data from three large prospective randomized clinical trials (n>11, 000) suggest that specific statins (mainly atorvastatin) ameliorate NAFLD/NASH and reduce CVD events twice as much as in those with normal liver function. Several biopsy studies have found that rosuvastatin use is related with significant histological ameliorating effects in the setting of NASH. Statin treatment may also protect from hepatocellular carcinoma (HCC) related to NAFLD/NASH. CONCLUSION: Since NAFLD/NASH patients have high CVD risk, they will probably require a statin. Thus, why not select a specific statins (atorvastatin or rosuvastatin, both generic now) that offer a substantial liver- and CVDrelated adverse event reduction? The administration of statins in these patients is as safe as in the general population.